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Trace Element Requirements for Adults on Long-Term Parenteral Nutrition
Lyn Howard, MB, FRCP, FACP, Medical & Research Director, The Oley Foundation
The research upon which the conclusions in this article are based is discussed in depth in “Autopsy tissue trace elements in 8 long-term parenteral nutrition patients who received the current U.S. Food and Drug Administration formulation,” Journal of Parenteral and Enteral Nutrition 31 (2007), 388–96. Tables 2 and 3 are reprinted from the JPEN article with permission.
Trace elements are minerals needed by the body to regulate metabolism (table 1). Like vitamins, they are
required in very small amounts, and large amounts may be toxic. In the early years of parenteral nutrition therapy, trace minerals were largely ignored; but as we extended our reliance on this therapy from weeks to months, deficiency syndromes of zinc, copper, chromium, and selenium were reported.
The questions then became: how much of these trace elements should we add to parenteral solutions, and how can we monitor patients for adequacy or excess?
Setting a Standard
In 1979, following a research meeting of human trace element experts, the American Medical Association (AMA) published recommendations for routine additions of zinc, copper, manganese, and chromium to parenteral formulas. A few years later a recommendation for selenium was also added. These experts made it clear that they expected their recommendations to be redefined and updated as new research information became available.
The Food and Drug Administration (FDA) has a fundamental obligation to protect the population from harmful drug effects. The FDA adopted the 1979 AMA recommendations for a parenteral multiple trace element (MTE) additive. This became the mandatory standard for any MTE commercial preparation used in the United States.
During the past thirty years, as predicted by the early scientists, new research information has led scientists to modify parenteral trace element recommendations. Table 2 shows the original 1979 AMA adult trace element guideline and the subsequent changes advised as new research data accumulated. The chief alterations were the much lower amounts of copper (upper level now one-third of 1979 amount) and manganese (upper level now one-eighth of 1979 amount).
Despite research data to support these changes, the FDA has not updated its recommended MTE formulation. Patients continue to receive the original 1979 formula unless their prescribing physicians order each trace element separately, which adds significant cost and room for error. The FDA is unlikely to change its designated MTE formula unless there is clear evidence of harm to patients receiving the 1979 MTE formula!
The question therefore becomes: is there evidence of harm and should long-term parenteral nutrition patients be asking for routine trace element monitoring? The answer is probably “yes” to harm and “no” to routine monitoring.
There are many pitfalls to routine clinical monitoring. First, trace element sampling and measurement requires a meticulous technique to avoid the risk of contamination leading to a misleading result. Second, the best test of nutrient adequacy is a measure of its biological function. If this function is normal, it indicates the nutrient is present in adequate amounts. Such a test is available for iron, iodine, and, in research settings, for selenium. For zinc, copper, chromium, and manganese, clinical tests of functional adequacy are not available.
Clinicians often turn to assessing trace elements by plasma or serum levels. Measuring these levels can be helpful in persons not receiving trace element supplements. In persons who are receiving trace element supplements, careful balance studies have shown no correlation of plasma or serum levels with body stores or adequate amounts in the tissue. Under these circumstances a blood level reflects the amount infused, not the amount needed. Furthermore, it is not known how long a specific trace element should be withheld to obtain an interpretable measurement.
This problem is compounded by the fact that many parenteral components are contaminated with varying amounts of trace elements. These nonprescribed sources can provide 10 to 100 percent of the daily requirement. Manganese and chromium are particularly common contaminants.
Because of these drawbacks, the question of trace element adequacy versus toxicity is most likely to be resolved in a research setting, rather than through routine clinical monitoring. Indeed, it was complex research balance studies that led to recommendations for a mild reduction in zinc and a significant reduction in copper from the 1979 guidelines.
Evidence of Harm
Manganese levels were known to be high but clinical toxicity was not documented until Fell and Reynolds described a neurological syndrome in children of irritability and Parkinsonian-like tremors which correlated with abnormal brain MRI findings.1 Both the symptoms and the MRI abnormalities slowly disappeared after manganese supplements were stopped. Interestingly the children’s liver function also improved as their manganese levels subsided, suggesting toxic manganese levels may contribute to parenteral nutrition liver dysfunction. Japanese studies have recently shown that 55 mcg/day of manganese is all that is needed to sustain normal blood levels. This may in fact be supplied by parenteral contaminants, making a routine parenteral manganese addition unnecessary.
In the Albany Medical College home parenteral nutrition (HPN) program we studied the cumulative effect of the 1979 MTE formulation in tissues obtained at autopsy. Long-term HPN consumers were asked to consider donating their bodies to this research if and when they died. Over ten years eight people died and their tissues were carefully sampled and sent to the Trace Element Unit of the Royal Infirmary, Glasgow, Scotland. Iron, zinc, copper, manganese, chromium, and selenium were measured by inductively coupled plasma methodology in heart, muscle, liver, and kidney tissues. These results were compared to tissue levels in forty-five control subjects who died without a chronic gastrointestinal disorder.
The eight Albany patients had lived on HPN for an average of fourteen years (range two to twenty-one years), and their HPN had contained the 1979 MTE formula (table 2). Their tissues showed normal amounts of iron and selenium, mild elevations of hepatic zinc, and major elevations of hepatic copper, manganese, and chromium. In four of the eight patients, hepatic copper reached the toxic levels characteristic of Wilson’s disease. This is a rare genetic syndrome of abnormal copper storage which leads to severe neurologic and hepatic damage.
While no clear-cut neurological syndrome was recognized in these patients, two died from liver failure. As their bilirubin levels started to rise, copper and manganese additions were discontinued in their parenteral solutions. This modification was obviously too late to change their hepatic copper and manganese accumulation. The unanswered question is: did excessive copper and manganese contribute to their liver failure or did they have another cause of liver disease that led to copper and manganese buildup, since these two elements are normally excreted in bile? Whatever the order of events, our tissue results strongly support the need for the FDA to revisit adult parenteral trace element guidelines for copper and manganese.
The high chromium levels are less of a concern because chromium toxicity has only been described in steel welders exposed to airborne chromium (Cr6 valency). Chromium is believed to be biologically active in an organic form as part of the insulin receptor. The measurement technique we used cannot distinguish the particular chemical form of this element. It seems likely that the excess chromium we measured was in a non-biologically active form. True assessment of chromium adequacy requires measurement of insulin sensitivity.
Where does this research data leave us? It strongly points to a risk of copper and manganese toxicity with the current FDA formulation. Clearly the FDA needs to revise its parenteral trace element recommendation. Traditionally this occurs when relevant professional organizations hold a high-level consensus conference at which all new scientific data are reviewed. Unfortunately, many national nutrition organizations consider parenteral trace elements too small a topic to warrant this consensus approach.
Consumers (long-term HPN patients) and their supporting professionals may have to band together and threaten to sue the FDA for a medication change. The threat of a class action suit has produced a rapid FDA response in the past. (Editor’s note: Micronutrients—vitamin and mineral additives—are being strongly considered as a topic for the 2009 A.S.P.E.N. research workshop. Stay tuned to www.oley.org for updates.)(*)
Meanwhile, adult HPNers need to request a trace element formula that approaches the newer scientific recommendations. Table 3 summarizes what we now prescribe for the Albany Medical Center HPN consumers. It is made from one mL of Multitrace®-4 (American Regent, Inc.; see table 2 on page 2) with added zinc and selenium.
1. Fell, J.M., Reynolds, A.P., Meadows, N., et al. “Manganese toxicity in children receiving long term parenteral nutrition.” Lancet 347 (1996), 1218–21
2. Reynolds, N., Blumsohn, A., Baxter, J.P., Houston, G., Pennington, C.R. “Manganese requirement and toxicity in patients on home parenteral nutrition.” Clinical Nutrition 17 (1998), 227–30.
* Update as of February 6, 2008:The author, Lyn Howard, MD, and Alan Buchman, MD, an Oley trustee, have been named co-chairs of the 2009 Clinical Nutrition Week Research Workshop which will address the parenteral requirements for micronutrients (trace elements, vitamins, and small additives such as choline and carnitine).
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